Substituted estratrienes as selectively active estrogens

ABSTRACT

This invention describes the new 9α-substituted estratrienes of general formula I 
     
       
         
         
             
             
         
       
     
     in which R 3 , R 7 , R 7′ , R 13 , R 16  as well as R 17  and R 17′  have the meanings that are indicated in the description and R 9  means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop- 1 -inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. 
     The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.

This application is a continuation application of U.S. Non-Provisionalapplication Ser. No. 10/458,735, filed on Jun. 11, 2003, which claimsthe benefit of the filing date of U.S. Provisional Application Ser. No.60/443,868, filled Jan. 31, 2003, both of which are incorporated byreference herein.

FIELD OF THE INVENTION

This invention relates to new compounds as pharmaceutical activeingredients, which have in vitro a higher affinity to estrogen receptorpreparations from rat prostates than to estrogen receptor preparationsfrom rat uteri and in vivo a preferential action in the ovary incomparison to the uterus, their production, their therapeutic use andpharmaceutical dispensing forms that contain the new compounds.

The chemical compounds are new, steroidal, tissue-selective estrogens.

BACKGROUND OF THE INVENTION

The efficiency of estrogens in the treatment ofhormone-deficiency-induced symptoms such as hot flashes, atrophy ofestrogen target organs and incontinence, as well as the successful useof estrogen therapies for prevention of bone mass loss in peri- andpostmenopausal women, is well documented and generally accepted (Gradyet al. 1992, Ann Intern Med 1117: 1016-1037). It is also well documentedthat estrogen replacement therapy in postmenopausal women or in womenwith ovarian dysfunction that is caused in some other way reduces therisk of cardiovascular diseases compared to women who are not treatedwith estrogen (Grady et al., loc. cit.).

In conventional estrogen or hormone replacement therapy (H ART), naturalestrogens, such as estradiol, and conjugated estrogens that consist ofequine urine are used either by themselves or in combination with agestagen. Instead of the natural estrogens, derivatives that areobtained by esterification, such as, e.g., 17β-estradiol-valerate, canalso be used.

Because of the stimulating action of the estrogens that are used on theendometrium, which results in an increase of the risk of endometrialcarcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986-1992),estrogen/gestagen combination preparations are preferably used inhormone replacement therapy. The gestagenic component in theestrogen/gestagen combination avoids hypertrophy of the endometrium, butthe occurrence of undesirable intracyclic menstrual bleeding is alsolinked to the gestagen-containing combination.

Selective estrogens represent a more recent alternative to theestrogen/gestagen combination preparations. Up until now, selectiveestrogens have been defined as those compounds that have anestrogen-like effect on the brain, bones and vascular system, owing totheir antiuterotropic (i.e., antiestrogenic) partial action, but they donot have a proliferative effect on the endometrium.

A class of substances that partially meet the desired profile of aselective estrogen is the so-called “Selective Estrogen ReceptorModulators” (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9):531-539). In this case, these are partial agonists of estrogen receptorsubtype “ERα.” This substance type is ineffective, however, with respectto the therapy of acute postmenopausal symptoms, such as, e.g., hotflashes. As an example of a SERM, the raloxifene that was recentlyintroduced for the indication of osteoporosis can be mentioned.

For the treatment of fertility disorders of women, frequently caused byovarian dysfunction that is caused by surgery, medication, etc., newpossible therapies are also opened up by the use of new selectiveestrogens. The in-vitro fertility treatment is a process that has beenestablished for more than 20 years. Numerous methods for treatingovarian-induced infertility with exogenic gonadotropins are known. Byadministration of gonadotropins such as FSH (FSH=follicle-stimulatinghormone), a stimulation of the ovaries, which is to make possible ahealthy follicular maturation, is to be produced.

The follicle is the functional unit of the ovary and has two purposes:it accommodates the oocytes and provides for the latter the possibilityfor growth and for maturation. Folliculogenesis comprises thedevelopment of an ovarian follicle from a primordial stage to acontinuously increasing antral follicle, which represents the last stagebefore ovulation. Only an optimally developed antral follicle canrelease a mature ovocyte by ovulation.

Patients with ovarian-induced infertility (PCOS=syndrome of polycysticovaries) suffer from a disrupted follicular maturation, which isassociated both with hormonal and ovulatory disruptions and withinadequately matured ovocytes. The number of primary and secondaryfollicles is approximately twice as high here as in the normal ovary(Hughesden et al., Obstet. Gynecol. Survey 37, 1982, pp. 59-77).

There are indications that the early development stages offolliculogenesis (which relates to the development of primordialfollicles to antral follicles) are gonadotropin-independent. It is notclearly explained how great the influence of known paracrine andautocrine factors is on early folliculogenesis (Elvin et al., Mol. Cell.Endocrinol. 13, 1999, pp. 1035-1048; McNatty et al., J. Reprod. Fertil.Suppl. 54, 1999, pp. 3-16).

Gonadotropins such as FSH are mainly involved in the last developmentstages of folliculogenesis in follicular maturation, i.e., in thedevelopment of the early antral follicle to a mature follicle that canundergo ovulation.

The in-vivo and in-vitro infertility is preferably treated withgonadotropins (FSH and antiestrogens) (White et al., J. Clin.Endocrinol. Metab. 81, 1996, pp. 3821-3824). In in-vitro fertilizationtreatment, oocytes are removed from preovulatory antral follicles to beable to mature in vitro into an ovocyte that can be fertilized. Afterfertilization and preembryonal development, one to three embryos areimplanted in the uterus of the woman.

In many respects, the treatment with exogenic gonadotropins isaccompanied by numerous risks and side effects. The greatest riskconsists in an overstimulation of the ovaries, which in severe cases canrepresent a serious danger to life (OHSS=Ovarian HyperstimulationSyndrome). Other side effects are the high costs of the in-vitrofertility treatment that must be paid by the couples. Negative sideeffects such as weight gain, bloatedness, nausea, vomiting and an as yetunknown long-term risk of developing cancer are attributed to thegonadotropin treatment.

One method to avoid the above-mentioned drawbacks and risks is to ensurethe maturation and stimulation in vivo of follicular growth in the caseof ovarian-induced infertility with a suitable active ingredient beforetreatment with exogenic gonadotropins begins.

Estrogen Receptor Beta (ERβ)

Several years ago, estrogen receptor β (ERβ) was discovered as a secondsubtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl.Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). Theexpression pattern of ERβ differs from that of the ERα (Kuiper et al.(1996), Endocrinology 138: 863-870). ERβ thus predominates over ERα inthe rat prostate, while ERα predominates over ERβ in the rat uterus. Thehighest concentrations of ERβ and mRNA were found in the ovaries (Couseet al. Endocrinology 138, 1997, pp. 4612-4613).

Other organ systems with comparatively higher ERβ-expression comprisethe bones (Onoe, Y. et al., 1997, Endocrinology 138: 4509-4512), thevascular system (Register, T. C., Adams, M. R. 1998, J. Steroid MolecBiol 64: 187-191), the urogenital tract (Kuiper, G. J. M. et al. 1997,Endocrinology 138: 863-870), the gastrointestinal tract(Campbell-Thopson 1997, BBRC 240: 478-483), as well as the testis(Mosselmann, S. et al. 1996 FEBS Lett. 392, 49-53) including thespermatides (Shugrue et al. 1998, Steroids 63: 498-504). The tissuedistribution suggests that estrogens regulate organ functions via ERβ.The fact that ERA is functional in this respect also follows by studiesin ERα- (ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bonemass loss in ERKO-mice, which can be eliminated by estrogen substitution(Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting, NewOrleans). Estradiol in the blood vessels of female ERKO mice alsoinhibits vascular media and smooth muscle cell proliferation (Iafrati,M. D. et al. 1997, Nature Medicine 3: 545-548). These protective actionsof estradiol are carried out in the ERKO mouse presumably via ERβ.

The fact that ERα and ERβ have a functionally different action wasconfirmed after successful production of αERKO and βERKO mice. ERαconsequently plays an important role in the adult uterus, in mammarygland tissue, in the negative regulation of the gonadotropin activity,while ERβ is mainly bonded in the processes of ovarian physiology,especially that of folliculogenesis and ovulation (Couse et al.,Endocrine Reviews 20, 1999, pp. 358-417).

Observations of βERKO mice provide an indication on a function of ERβ inthe prostate and bladder: in the case of older male mice, symptoms ofprostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, ProcNatl Acad Sci 95: 15677-15682). In addition, female ERKO mice (Lubahn,D. B. et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKOmice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well as femaleβERKO mice (Krege, J. H., 1998, Proc Natl Acad Sci 95: 15677-15682) havefertility disorders. Consequently, the important function of estrogenswith respect to maintaining testis and ovary functions as well asfertility is confirmed.

It was possible to achieve a selective estrogenic action on specifictarget organs by subtype-specific ligands based on the different tissueor organ distribution of the two subtypes of the ERs. Substances with apreference for ERβ compared to ERα in the in-vitro receptor binding testwere described by Kuiper et al. (Kuiper et al. (1996), Endocrinology138: 863-870). A selective action of subtype-specific ligands of theestrogen receptor on estrogen-sensitive parameters in vivo was notpreviously shown.

The object of this invention is therefore to prepare compounds that havein vitro a dissociation with respect to the binding to estrogen receptorpreparations from rat prostates and rat uteri. The compounds are to showin vitro a higher affinity to estrogen receptor preparations from ratprostates than to estrogen receptor preparations from rat uteri.

The ERβ-specific compounds are to produce in vivo a profertility actionin the ovary. At the same time, the compounds are to exhibit adissociation with respect to ovary action in comparison to uterusaction. The compounds according to the invention are to have a certainprotective action against hormone-deficiency-induced bone mass loss incomparison to uterus-stimulating action.

In the broader sense, a structure-action relationship, which allows foraccess to compounds that have the above-formulated pharmacologicalprofile, is to be made available by this invention. The compoundsaccording to the invention are to produce enhanced fertility in theovary while at the same time affecting the uterus very little in casesof ovarian-associated infertility.

According to the invention, the object above is achieved by theprovision of 9α-substituted estra-1,3,5(10)-triene derivatives ofgeneral formula I

in which radicals R³, R⁷, R^(7′), R⁹, R¹³, R¹⁶ as well as R¹⁷ andR^(17′), independently of one another, have the following meaning:

-   -   R³ means a hydrogen atom or a group R¹⁸, in which        -   R¹⁸ means a straight-chain or branched-chain, saturated or            unsaturated hydrocarbon radical with up to 6 carbon atoms, a            trifluoromethyl group, an optionally substituted aryl,            heteroaryl or aralkyl radical, an acyl radical COR¹⁹, in            which R¹⁹ is an optionally substituted, straight-chain or            branched-chain hydrocarbon radical with up to 10 carbon            atoms that is saturated or unsaturated in up to three places            and optionally partially or completely halogenated, or        -   R¹⁸ means a group R²⁰SO₂, in which            -   R²⁰ is an R²¹R²²N group, whereby R²¹ and R²²,                independently of one another, mean a hydrogen atom, a                C₁-C₅-alkyl radical, a group C(O)R²³, in which R²³ means                an optionally substituted, straight-chain or                branched-chain hydrocarbon radical with up to 10 carbon                atoms that is saturated or unsaturated in up to three                places and is optionally partially or completely                halogenated, an optionally substituted C₃-C₇-cycloalkyl                radical, an optionally substituted                C₄-C₁₅-cycloalkylalkyl radical or an optionally                substituted aryl, heteroaryl or aralkyl radical, or,                together with the N atom, a polymethylenimino radical                with 4 to 6 C atoms or a morpholino radical,    -   R⁷ and R^(7′), in each case independently of one another, are a        hydrogen atom or a halogen atom,    -   R⁹ is a straight-chain or branched-chain alkenyl or alkinyl        radical with 2 to 6 carbon atoms, which optionally can be        partially or completely fluorinated,    -   R¹³ is a methyl group or an ethyl group,    -   R¹⁶ is a hydroxy group or a group R¹⁸O—, R²⁰SO₂— or OC(O)R²³        with R¹⁸, R²⁰ and R²³ in each case in the meaning that is        indicated under R³,    -   R¹⁷ and R^(17′), in each case independently of one another, are        a hydrogen atom or a halogen atom,    -   R¹⁶ can in each case be in α- or β-position.

According to a variant of the invention, gonatriene derivatives arepreferred, in which R⁷ and R^(7′) are a hydrogen atom, R⁹ is a vinyl,ethinyl or prop-1-inyl group, R¹⁶ is a hydroxy group, and R¹⁷ andR^(17′) in each case are a hydrogen atom.

In addition, the following combinations of halogen substitution,preferably fluorine, in C-atoms 7 and 17 are preferred: 7-mono or 7-diand R¹⁷ as well as R^(17′), in each case a hydrogen, 17-mono or 17-diand R⁷ as well as R^(7′), in each case a hydrogen as well as7-mono/17-mono, 7-mono/17-di, 7-di/17-mono, 7-di/17-di. The 7α-positionor the 17β-position is preferred in the monofluorine compounds.

Another variant of the invention in particular calls for compounds inwhich R¹⁶ stands for a group R¹⁸O— or R²⁰SO₂—O— with R¹⁸ and R²⁰ in eachcase in the meaning that is indicated under R³.

Preferred according to this invention are the following compounds:

-   9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol-   9α-Allyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol-   3-Methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol-   9α-Allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol-   18a-Homo-3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol-   18a-Homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol-   9α-(2′,2′-Difiluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol-   9α-(2′,2′-Difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16α-ol-   16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate-   9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate-   18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate-   18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5 (10)-trien-3yl-sulfamate-   9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate-   9α-Allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate-   18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate-   18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate-   16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate-   9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate-   18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5    (10)-trien-3yl-(N-acetyl)-sulfamate-   18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate-   9α-(Prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α-diol-   9α-(n-Propyl)-estra-1,3,5(10)-triene-3,16α-diol-   9α-Ethinyl-estra-1,3,5(10)-triene-3,16α-diol-   9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate-   18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate-   16α-Valeroyloxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol-   16α-Acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol-   18a-Homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol-   7α-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-   7α-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol-   17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-   17β-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-   18a-Homo-17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol

Other possible configurations of this invention will emerge from thesubclaims.

Hydrocarbon radical R¹⁸ is, for example, a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl,or hexyl radical.

Alkoxy groups OR¹⁸ in the compounds of general formula I in each casecan contain 1 to 6 carbon atoms, whereby methoxy, ethoxy, propoxy,isopropoxy and t-butyloxy groups are preferred.

Representatives of the C₁-C₅-alkyl radicals R²¹ and R²² are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyland neopentyl.

As representatives of straight-chain or branched-chain hydrocarbonradicals R²³ with 1 to a maximum of 10 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, heptyl, hexyl, and decyl can be mentioned; methyl,ethyl, propyl and isopropyl are preferred.

As a C₃-C₇-cycloalkyl group, a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl group can be mentioned.

A C₄-C₁₅-cycloalkylalkyl radical has 3 to 7 carbon atoms in thecycloalkyl portion; typical representatives are the cycloalkyl groupsthat are mentioned directly above. The alkyl portion has up to 8 carbonatoms.

As examples of a C₄-C₁₅-cycloalkylalkyl radical, the cyclopropylmethyl,cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl groups, etc., canbe mentioned.

In terms of this invention, an aryl radical is a phenyl, 1- or2-naphthyl radical; the phenyl radical is preferred.

Aryl always also includes a heteroaryl radical. Examples of a heteroarylradical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, thepyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

As substituents that can be present on an aryl or heteroaryl radical,for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-,trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C₁₋₈alkyl) or di(C₁₋₈ alkyl)amino, whereby both alkyl groups are identicalor different, di(aralkyl)amino, whereby both aralkyl groups areidentical or different, carboxyl, carboxyalkoxy, C₁-C₂₀-acyl orC₁-C₂₀-acyloxy groups can be mentioned.

An aralkyl radical is a radical that contains in the ring up to 14,preferably 6 to 10, C atoms, and in the alkyl chain 1 to 8, preferably 1to 4, C atoms. Thus, as aralkyl radicals, for example, benzyl,phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl,and pyridylpropyl are suitable.

The alkyl groups or hydrocarbon radicals can be partially or completelysubstituted by 1-5 halogen atoms, hydroxy groups or C₁-C₄-alkoxy groups.

A vinyl or allyl radical is primarily defined with a C₂-C₆-alkenylradical.

A C₂-C₆-alkinyl radical is preferably defined as an ethinyl radical or apropl-1-inyl radical.

C₁₋₁₀-Acyl radicals mean, for example, acetyl, propionyl, butyryl,valeroyl, isovaleroyl, pivaloyl, hexanoyl, octyl, nonyl, or decanoyl.

One or two hydroxyl groups at C atoms 3 and 16 can be esterified with analiphatic, straight-chain or branched-chain, saturated or unsaturatedC₁-C₁₄-mono- or polycarboxylic acid or an aromatic carboxylic acid.

Suitable as such carboxylic acids for esterification are, for example:

Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyricacid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid,lauric acid, myristic acid, acrylic acid, propionic acid, methacrylicacid, crotonic acid, isocrotonic acid, oleic acid, and elaidic acid.

Esterification with acetic acid, valeric acid or pivalic acid ispreferred.

Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaricacid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacicacid, maleic acid, fumaric acid, muconic acid, citraconic acid, andmesaconic acid.

Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalicacid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid,hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, andisonicotinic acid.

Esterification with benzoic acid is preferred.

As prodrugs, the esters of the 9α-substituted estratrienes according tothe invention have advantages compared to the unesterified activeingredients with respect to their method of administration, their typeof action, strength and duration of action.

Especially the sulfamates of 9α-substituted estratrienes according tothe invention have pharmacokinetic and pharmacodynamic advantages.Related effects were already described in other steroid-sulfamates (J.Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest.Drugs 7, 575-589 (1998)).

In this patent application, steroids on which the 9α-substitutedestra-1,3,5(10)-triene skeleton is based are described for the treatmentof estrogen receptor β-mediated disorders and conditions as selectiveestrogens, which have in-vitro dissociation with respect to theirbinding to estrogen receptor preparations from rat prostates and ratuteri and which have in vivo preferably a dissociation with respect toovary action in comparison to uterus action. In addition, the compoundshave a certain protective action against hormone-deficiency-induced bonemass loss.

It was found that the 9α-substituted estra-1,3,5(10)-trienes accordingto general formula I are suitable as selective estrogens for thetreatment of various conditions and disorders that are characterized bya higher content of estrogen receptor β than estrogen receptor α in thecorresponding target tissue or target organ.

The invention also relates to pharmaceutical preparations that containat least one compound of general formula I (or physiologicallycompatible addition salts with organic and inorganic acids thereof) andthe use of the compounds of general formula I for the production ofpharmaceutical agents, especially for the indications mentioned below.

The new selective estrogens that are described here can be used asindividual components in pharmaceutical preparations or in combinationespecially with gestagens. Especially preferred is the combination ofselective estrogens with ERα-selective antiestrogens that areperipherally-selectively active, i.e., that do not pass through theblood-brain barriers, as well as with selective estrogen receptormodulators (SERM). The ERβ-selective compounds according to theinvention can be used in particular for the production of pharmaceuticalagents for treating fertility disorders, for prevention and therapy ofprostate hyperplasia, for prevention and treatment ofhormone-deficiency-induced mood swings in women and men and for use inhormone replacement therapy (HRT) in men and women.

A therapeutic product that contains an estrogen and a pure antiestrogenfor simultaneous, sequential or separate use for the selective estrogentherapy of perimenopausal or postmenopausal conditions is alreadydescribed in EP-A 0 346 014.

Because of their dissociation of action in the ovary in comparison tothe action of the uterus, the substances and the pharmaceutical agentsthat contain them are especially suitable for the treatment in the caseof ovarian dysfunction that is caused by surgery, medication, etc., suchas female infertility for stimulation of folliculogenesis for treatmentby itself in terms of enhanced fertility, for supporting in-vitrofertility treatment (IVF) in connection with an in-vivo treatment andfor treatment of ovarian-induced disorders in later age (“latefertility”) as well as for treatment of hormone-deficiency-inducedsymptoms.

The substances are also suitable for therapy of ovarian diseases such aspolycystic ovarian syndrome, POF (premature ovarian failure) syndromesand ovulation disorders.

Finally, the compounds of general formula I can be used in connectionwith selective estrogen receptor modulators (SERM) or raloxifene,specifically in particular for use in hormone replacement therapy (HRT)and for treatment of gynecological disorders.

The substances are also suitable as individual components for thetreatment of perimenospausal and postmenopausal symptoms, in particularhot flashes, sleep disturbances, irritability, mood swings,incontinence, vaginal atrophy and hormone-deficiency-induced mentaldisorders. The substances are also suitable for hormone substitution andfor the therapy of hormone-deficiency-induced symptoms in ovariandysfunction that is caused by surgery, medication, etc.

In addition, the substances can also be used to preventhormone-deficiency-induced bone mass loss and osteoporosis, to preventcardiovascular system diseases, in particular vascular diseases such asarteriosclerosis, high blood pressure and to preventhormone-deficiency-induced neurodegenerative diseases, such asAlzheimer's disease, as well as hormone-deficiency-induced impairment ofmemory and learning capacity.

In addition, the substances can be used as active ingredients inpreparations for treating inflammatory diseases and diseases of theimmune system, in particular autoimmune diseases, such as, e.g.,rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease andother inflammatory intestinal diseases, inflammatory diseases of theskin, such as psoriasis, as well as for treating endometriosis.

In addition, the substances are effective against inflammatory diseasesof the respiratory system, the lungs and bronchial tubes, such as, e.g.,asthma.

The medication is suitable for therapy and prophylaxis ofestrogen-deficiency-induced diseases both in women and in men.

In men, the compounds are especially suitable for therapy ofhormone-deficiency-induced bone mass loss and osteoporosis, forprevention of cardiovascular diseases, in particular vascular diseasessuch as arteriosclerosis, high blood pressure and for prevention ofhormone-deficiency-induced neurodegenerative diseases, such asAlzheimer's disease, as well as hormone-deficiency-induced impairment ofmemory and learning capacity, and are suitable for prevention andtherapy of prostate hyperplasia.

The substances can be used for prophylaxis and therapy of age-relateddysfunctions or diseases of men. In particular, they can be used forprevention and treatment of an age-related drop of androgens, such astestosterone and DHEA, as well as of the growth hormone.

In addition, the medication can be used for treating inflammatorydiseases and diseases of the immune system, in particular autoimmunediseases in men, such as, e.g., rheumatoid arthritis, MS (multiplesclerosis) and Crohn's disease and other inflammatory intestinaldiseases, as well as inflammatory diseases of the respiratory system,the lungs, and the bronchial tubes. The amount of a compound of generalformula I that is to be administered fluctuates within a wide range andcan cover any effective amount. On the basis of the condition that is tobe treated and the type of administration, the amount of the compoundthat is administered can be 0.01 μg/kg-100 mg/kg of body weight,preferably 0.04 μg/kg-1 mg/kg of body weight, per day.

In humans, this corresponds to a dose of 0.8 μg to 8 g, preferably 3.2μg to 80 mg, daily.

According to the invention, a dosage unit contains 1.6 μg to 2000 mg ofone or more compounds of general formula I.

The compounds according to the invention and the acid addition salts aresuitable for the production of pharmaceutical compositions andpreparations. The pharmaceutical compositions or pharmaceutical agentscontain as active ingredients one or more of the compounds according tothe invention or their acid addition salts, optionally mixed with otherpharmacologically or pharmaceutically active substances. The productionof the pharmaceutical agents is carried out in a known way, whereby theknown and commonly used pharmaceutical adjuvants as well as othercommonly used vehicles and diluents can be used.

As such vehicles and adjuvants, for example, those are suitable that arerecommended or indicated in the following bibliographic references asadjuvants for pharmaceutics, cosmetics and related fields: UllmansEncyklopädie der technischen Chemie [Ullman's Encyclopedia of TechnicalChemistry], Volume 4 (1953), pages 1 to 39; Journal of PharmaceuticalSciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald,Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants forPharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 andff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetikund angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics,Cosmetics and Related Fields], Cantor KG, Aulendorf in Württemberg 1971.

The compounds can be administered orally or parenterally, for exampleintraperitoneally, intramuscularly, subcutaneously or percutaneously.The compounds can also be implanted in the tissue.

For oral administration, capsules, pills, tablets, coated tablets, etc.,are suitable. In addition to the active ingredient, the dosage units cancontain a pharmaceutically compatible vehicle, such as, for example,starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

For parenteral administration, the active ingredients can be dissolvedor suspended in a physiologically compatible diluent. As diluents, veryoften oils with or without the addition of a solubilizer, a surfactant,a suspending agent or an emulsifying agent are used. Examples of oilsthat are used are olive oil, peanut oil, cottonseed oil, soybean oil,castor oil and sesame oil.

The compounds can also be used in the form of a depot injection or animplant preparation, which can be formulated so that a delayed releaseof active ingredient is made possible.

As inert materials, implants can contain, for example, biodegradablepolymers, or synthetic silicones such as, for example, silicone rubber.In addition, for percutaneous administration, the active ingredients canbe added to, for example, a patch.

For the production of intravaginal systems (e.g., vaginal rings) orintrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that areloaded with active compounds of general formula I for localadministration, various polymers are suitable, such as, for example,silicone polymers, ethylene vinyl acetate, polyethylene orpolypropylene.

To achieve better bio-availability of the active ingredient, thecompounds can also be formulated as cyclodextrin clathrates. For thispurpose, the compounds are reacted with α-, β-, or γ-cyclodextrin orderivatives of the latter (PCT/EP95/02656).

According to the invention, the compounds of general formula I can alsobe encapsulated with liposomes.

Methods Estrogen Receptor Binding Studies:

The binding affinity of the new selective estrogens was tested incompetitive experiments with use of ³H-estradiol as a ligand to estrogenreceptor preparations from rat prostates and rat uteri. The preparationof prostate cytosol and the estrogen receptor test with prostate cytosolwas carried out as described by Testas et al. (1981) (Testas, J. et al.,1981, Endocrinology 109: 1287-1289).

The preparation of rat uterus cytosol as well as the receptor test withthe ER-containing cytosol were basically performed as described by Stackand Gorski (1985) (Stack, Gorski 1985, Endocrinology 117, 2024-2032)with some modifications as described in Fuhrmann et al. (1995)(Fuhrmann, U. et al. 1995, Contraception 51: 45-52).

The substances that are described here have higher binding affinity tothe estrogen receptor of rat prostates than to estrogen receptors of ratuteri. In this case, it is assumed that ERβ predominates in the ratprostates over ERα, and ERα predominates in rat uteri over ERβ. Table 1shows that the ratio of the binding to prostate and uterus receptorsqualitatively coincides with the quotient of relative binding affinity(RBA) to human ERβ and ERα of rats (according to Kuiper et al. (1996),Endocrinology 138; 863-870) (Table 1).

TABLE 1 Rat Rat uterus prost. prost. hERα hERβ ERβ/ ER ER ER/uterusEstrogen RBA* RBA* ERα (RBA) (RBA) ER Estradiol 100 100 1 100 100 1Estrone 60 37 0.6 3 2 0.8 17α-Estradiol 58 11 0.2 2.4 1.3 0.5 Estriol 1421 1.5 4 20 5 5-Androstene- 6 17 3 0.1 5 50 diol Genisteine 5 36 7 0.110 100 Coumestrol 94 185 2 1.3 24 18 *Cited from: Kuiper et al. (1996),Endocrinology 138: 863-870

Table 2 shows the results for 4 of the9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol derivatives (compounds 1; 2;4; 5) according to the invention.

TABLE 2 RBA RBA Compound Rat Uterus Rat Prostate9α-Vinyl-estra-1,3,5(10)- 1.2 100 3,16α-diol (1)9α-Vinyl-estra-1,3,5(10)-17F- 2 200 3,16α-diol (2) 9α-Di-F-Vinyl-estra-0.2 4 1,3,5(10)-3,16α-diol (4) 9α-Di-F-Vinyl-estra- 0.2 61,3,5(10)-13-Methyl-3,16α- diol 5

Compounds 1; 2; 4; 5 according to the invention show a higher bindingaffinity to the estrogen receptor of rat prostates than to the estrogenreceptor of rat uteri.

In addition, the predictability of the prostate-ER versus the uterus-ERtest system was confirmed with respect to tissue-selective action byin-vivo studies. Substances with a preference for prostate-ER aredissociated in vivo preferably with respect to ovary and uterus actionas well as pituitary gland action in favor of action on the ovary.

Studies for Dissociation of Action of the Ovary/Uterus and PituitaryGland

The studies with respect to the action on uterus growth and ovulation(indirect effect by influencing the secretion of pituitary glandhormones) are performed on adult female rats (body weight of 220-250 g).The substances are subcutaneously administered four times on fourconsecutive days. The first administration is carried out in themetestrus. One day after the last administration, the autopsy is carriedout. The number of ovocytes in the tube (effect on the ovulation) aswell as the uterus weight are determined.

While estradiol produces a dose-dependent ovulation inhibition and anincrease in uterus weight with an ED₅₀ of 0.004 mg/kg of body weight,substance 1 according to the invention up to a dose of 0.4 mg/kg of bodyweight does not exert any effect on ovulation and uterus weight.

Ovary Studies:

The substances were tested in vivo on hypophysectomized juvenile rats.In a modification of this operative method, a GnRH antagonist isadministered to the animals. It is examined whether the substancestimulates follicular proliferation (maturation) in the ovary. The ovaryweight is the measurement parameter.

In each case, five animals (body weight 40-50 g) are assigned randomlyto the treatment groups. The animals are fed as much as they want with astandard diet (altromin) in Makrolon cages in air-conditioned rooms witha lighting program (10 hours of darkness, 14 hours of light) and aregiven acidified tap water to drink. For the s.c administration, the testsubstance as well as the control substance (estradiol E2) are dissolvedin benzylbenzoate/castor oil (1+4 v/v).

Juvenile female rats are either hypophysectomized on day 0 andsubcutaneously treated (administration 1×daily) from day 1 to day 4 withestradiol, compound 1 or 2 according to the invention, or subcutaneouslytreated (administration 1×daily) with a vehicle (castor oil/benzylbenzoate). In the modified version of the method, 0.5 mg/animal/day ofCetrorelix is administered to the animals simultaneously with compound 2or the vehicle and the control substance estradiol over four days oftreatment. In both cases, the animals are sacrificed 24 hours after thelast administration, and the ovary weight is determined.

0.5 mg/animal/day of compound 1 that is administered subcutaneously over4 days produces a comparable increase in ovary weight inhypophysectomized animals like estradiol with a dose of 0.1mg/animal/day. The vehicle does not produce any effect.

Substance 1 according to the invention thus shows a clear dissociationof action in the ovary in comparison to the uterus action and thepituitary gland action and is excellently suited for the preferredindication, the treatment of female infertility, because of itsfollicle-stimulating action.

In the GnRH antagonist-treated animals, concentrations of 0.1 and 0.3mg/animal/day of compound 2 in the ovary already show the same action asthe dose of 1 mg/animal/day of estradiol that is used (FIG. 1). Evenlower dosages (0.01, 0.03 mg/animal/day) show an ovary action and caneliminate the antagonistic effect of Cetrorelix (FIG. 2).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: Illustrates the Change in the ovary weight under the influenceof a GnRH antagonist in the treatment with estradiol (Sub3) or variousdosages of compound 2

FIG. 2: Illustrates the Positive effect of compound 2 in low dosage onthe ovary weight during a combination treatment with the GnRH antagonistCetrorelix

Key to FIG. 1: Ovar=Ovary

Feuchtgewicht (%)=Moist weight (%)0,1 mg=0.1 mg0,3 mg=0.3 mg1,0 mg=1.0 mg

Key to FIG. 2: Ovar=Ovary

Feuchtgewicht (%)=Moist weight (%)0,003 mg=0.003 mg0,01 mg=0.01 mg0,03 mg=0.03 mg0,1 mg=0.1 mg

Substance 2 according to the invention thus also shows a clearlypositive action on the ovary by stimulating the follicular maturationand therefore is also suitable for the treatment of female sub- orinfertility.

Production of the Compounds According to the Invention

For the production of the compounds of general formula I according tothe invention, primarily two synthesis strategies that can generally beapplied are used.

On the one hand, in particular 3,16-protected derivatives ofestra-1,3,5(10)-triene-3,16ξ-diols, but also optionally the free diols,can be used for modifications of individual positions of the steroidskeleton.

On the other hand, correspondingly modified estrone analogs, which canbe obtained in large numbers in known ways [for a typical synthesisprocess, see J. Chem. Soc. Perk. 1, 1973, 2095 for C(9); Steroids 54,1989, 71 for C(7)], include a flexible access to the compounds accordingto the invention by transposition of oxygen functionality (Z. Chem.1970, 221) from C(17) to C(16).

For the case of the 3-methyl ether, after the ketone is converted into asulfonyl hydrazone, the formation of the C(16)-C(17) olefin (Z. Chem.1970, 10, 221 ff; Liebigs Ann. Chem. 1981, 1973 ff), in whichhypobromide is stored in a regio-/stereo-controlled way, is carried outin the simplest case by reaction with phenyl sulfonylhydrazide, in adegradation reaction. Reductive dehalogenation and removal of theprotective group of C(3) yield the 16β-alcohol, which can be convertedaccording to known methods into the 16α-epimer.

Another variant for the introduction of the hydroxyl group at C-atom 16is in the hydroboration of the 16(17)-double bond with stericallyexacting boranes. It is known of this reaction that it results in16-oxidized products (Indian J. Chem. 1971, 9, 287-8). Consequently, thereaction of estra-1,3,5(10),16-tetraenes with, for example,9-borabicyclo[3.3.1]nonane after oxidation with alkaline hydrogenperoxide yields 16α-hydroxyestratrienes. To a lesser extent, theepimeric 16β-hydroxy steroids are formed in this reaction. After thecleavage of the 3-methoxy group, estra-1,3,5(10)-triene-3,16α-diols areobtained. By inversion of the configuration at C-atom 16, e.g., byMitsunobu reaction (synthesis 1980, 1), in turn the16β-hydroxyestratrienes are obtained.

For further production possibilities of the C(16)-C(17) olefinicintermediate stage, see also DE 199 06 159 A1.

The introduction of fluorine substituents is carried out vianucleophilic substitution reactions of hydroxyl groups with fluoroaminereagents (Org. React. 1974, 21, 158-173). If the hydroxyl groups areconverted into the corresponding tosylates in advance, then thefluorinated compounds are obtained by reaction withtetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, pp. 4728-4755).Fluorine compounds are also accessible by reaction of correspondingalcohols with diethylamino sulfur trifluoride (DAST) (U.S. Pat. No.3,976,691). Geminal difluorine compounds are produced, for example, byreaction of carbonyl compounds with sulfur tetrafluoride (U.S. Pat. No.3,413,321) or diethylamino sulfur trifluoride (DAST) (U.S. Pat. No.3,979,691).

For synthesis of the 9α-substituted17β-fluoroestra-1,3,5(10)-triene-3,16-diols according to the invention,17-oxo-estra1,3,5(10)-trienes are converted into the17,17-difluoroestra-1,3,5(10)-trienes (U.S. Pat. No. 3,976,691). Thethus accessible 17,17-difluoroestra-1,3,5(10)-trienes are converted bytreatment with aluminum oxide into 17-fluoroestra-1,3,5(10),16-tetraene(U.S. Pat. No. 3,413,321). Another possibility for the production offluoro-olefins exists in the reaction of the corresponding ketones withdiethylamino sulfur trifluoride (DAST) in the presence of polarcatalysts, such as fuming sulfuric acid (U.S. Pat. No. 4,212,815). Thereaction of 17-fluoroestra-1,3,5(10),16-tetraenes with boranes andsubsequent oxidation with alkaline hydrogen peroxide yields the17′-fluoroestra-1,3,5(10)-trien-16α-ols (Org. React. 1963, 13, 1-54).

Access to the 9α-alkenyl- or 9α-alkinyl-substitutedestra-1,3,5(10)-triene-3,16α-diols according to the invention is carriedout first from the 3,16-dihydroxy-estra-1,3,5(10)-trienes that areprotected in 3- and 16-position. By reaction with trimethyl silylcyanide in the presence of lithium perchlorate, the regio- andstereoselective introduction of a 9α-cyano grouping (Synlett, 1992,821-2) is carried out. After the protective groups are cleaved, the9α-cyano compound is converted by reduction first into a 9α-formylcompound and then by a Wittig reaction (Org. React. Vol. 14, 270) intothe 9α-alkenyl- or 9α-alkinyl-substituted compound.

The estratriene sulfamates according to the invention are accessible ina way that is known in the art from the corresponding hydroxy steroidsby esterification with sulfamoyl chlorides in the presence of a base [Z.Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)].

Subsequent acylation of the sulfamate group results in the(N-acyl)sulfamates according to the invention. For the(N-acyl)sulfamates, pharmacokinetic advantages were already detected(cf. DE 195 40 233 A1).

The regioselective esterification of polyhydroxylated steroids withN-substituted and N-unsubstituted sulfamoyl chlorides is carried outafter partial protection of those hydroxyl groups that are to remainunesterified. Silyl ethers have turned out to be protective groups withselective reactivity that is suitable for this purpose since these silylethers are stable under the conditions of sulfamate formation, and thesulfamate group remains intact when the silyl ether(s) is (are) againcleaved for regeneration of the (residual) hydroxyl group(s) stillcontained in the molecule (Steroids 61, 710-717 (1996)).

The production of the sulfamates according to the invention with anadditional hydroxyl group in the molecule is also possible in that thestarting material is suitable hydroxy-steroid ketones. First, dependingon the goal, one or more hydroxyl groups that are present are subjectedto sulfamoylation. Then, the sulfamate groups optionally can beconverted with a desired acyl chloride in the presence of a base intothe (N-acyl)sulfamates in question. The now present oxosulfamates oroxo-(N-acyl)sulfamates are converted by reduction into the correspondinghydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717(1996)), Sodium borohydride and the borane-dimethyl sulfide complex areconsidered as suitable reducing agents.

The examples below are used for a more detailed explanation of theinvention.

Analogously to the degradation of the 9α-vinyl grouping, other compoundsof general formula I can be obtained with use of reagents that arehomologous to the reagents that are described in the examples.

Etherification and/or esterification of free hydroxy groups is carriedout according to the methods that are common to one skilled in the art.

EXAMPLE 1 9α-Vinylestra-1,3,5(10)-triene-3,16α-diol Stage 19α-Cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate

A solution of 2.21 g (9.73 mmol) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 80 ml of methylene chlorideis added drop by drop while being stirred to a suspension that consistsof 2.13 g (6.49 mmol) of 3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate,2.07 ml (16.54 mmol) of trimethylsilyl cyanide and 0.14 g of lithiumperchlorate in 100 ml of methyl ene chloride. The reaction mixture isgreen in color. After 1 hour of reaction time at room temperature, themixture is mixed with sodium bicarbonate solution. The separated organicphase is washed with water and concentrated by evaporation in a vacuum.The product mixture is chromatographed on silica gel (cyclohexane/ethylacetate, 6/1). 0.44 g (21%) of9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate is obtained.

Stage 2 9α-Cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate

7.51 g (50.1 mmol) of sodium iodide and 8.87 ml (70.14 mmol) oftrimethylchlorosilane are added to a solution that consists of 0.59 g(1.67 mmol) of 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetatein 30 ml of acetonitrile while being stirred in an argon atmosphere.After about 3 hours at 60-70° C., the reaction is completed. Thereaction solution is added to sodium hydrogen sulfite solution andextracted with ethyl acetate. The organic phase is washed several timeswith water, dried on MgSO₄ and concentrated by evaporation in a vacuumto the dry state.

The crude product is chromatographed on silica gel (cyclohexane/ethylacetate, 4/1). 0.43 g (76%) of product is obtained.

Stage 3 3,16α-Dihydroxyestra-1,3,5(10)-triene-9 carbonitrile

At room temperature, 0.43 g (1.27 mmol) of9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate is stirred for 2hours with 1.0 g (7.24 mmol) of potassium carbonate in 40 ml of methanol(1% water). Then, the methanol is distilled off in a vacuum, and theorganic residue is dissolved in methylene chloride. The organic phase iswashed with water and concentrated by evaporation. 3.5 g (93%) of9α-cyano-estra-1,3,5(10)-triene-3,16α-diol is obtained.

Stage 4 3,16α-Dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde

A suspension that consists of 100 mg (0.34 mmol) of3,16α-dihydroxyestra-1,3,5(10)-triene-9 carbonitrile in 40 ml of tolueneis cooled to about −20° C. while being stirred. After 0.9 ml (1.35 mmol)of diisobutylaluminium hydride is added, the reaction is mixed afterabout 10 minutes with sodium bicarbonate solution, filtered over Celite,and the filtering adjuvant is extracted again with ethyl acetate. Thecombined organic phases are washed with water. By concentration byevaporation of the solution in a vacuum, 84.6 mg of a light yellow foamis obtained. The product that is contained in the mixture corresponds toa yield of about 52% of theory and is used without furtherchromatographic working-up in the next stage.

Stage 5 9α-Vinylestra-1,3,5(10)-triene-3,16α-diol

Under inert-gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethylphosphonium iodide and 0.24 g (8 mmol) of sodium hydride (80% inparaffin oil) in 20 ml of DMSO in an ultrasound bath are brought toreaction at about 55° C. After 10 minutes, 80 mg (0.16 mmol, about 60%)of 3,16α-dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde is added to thesolution, and the mixture is allowed to react for 60 more minutes atabout 55° C. in an ultrasound bath. After water is added, it isextracted with ethyl acetate. The collected organic phases are washedwith water, and the organic phase is concentrated by evaporation in avacuum.

The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate, 2/1) and subsequent recrystallization fromchloroform. Yield: 24 mg (50%), melting point 88-95° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS): 9.00 (s, 3-OH); 6.98 (d, J=8.6 Hz, H-1);6.49 (dd, J=8.6/2.7 Hz, H-2); 6.41 (d, J=2.7 Hz, H-4); 6.25 (dd,J=17.2/10.5 Hz, —CH═CH₂); 5.00 (dd, 10.5/1.9 Hz, —CH═CH₂ ; 4.47 (d, 4.69Hz, 16α-OH); 4.45 (dd, 17.2/1.9 Hz, —CH═CH₂ ); 4.24 (m, 16β-H); 2.68 (m,H-6); 0.69 (s, H-18)

EXAMPLE 2 9α-Vinyl-18a-homo-estra-1,3,5(10)-triene-3,16α-diol Stage 13,16α-Bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

1.03 g (2.26 mmol) of3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene, 48.2mg (0.45 mmol) of lithium perchlorate and 0.71 ml (5.66 mmol) oftrimethylsilyl cyanide are introduced into 10 ml of methylene chloride(molecular sieve) and cooled under inert gas to about −70° C. whilebeing stirred. Then, 0.77 g (3.39 mmol) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dissolved in 65 ml ofmethylene chloride, is added in drops within 1 hour. After about 1 hour(heating to room temperature), the reaction solution is mixed withsodium bicarbonate solution, and the reaction products are extractedwith methylene chloride. The crude product that is obtained byconcentration by evaporation of the organic phases is purified bychromatography. After chromatography on silica gel (cyclohexane/ethylacetate, 4/1), 0.74 g (68% of theory) of product is obtained.

Stage 2 3,16α-Dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde

1.3 g (2.7 mmol) of3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrileis dissolved in 40 ml of toluene and mixed at room temperature underinert gas with 7.2 ml (10.8 mmol) of diisobutylaluminum hydride solution(1.5 M in toluene). After a reaction time of 30 minutes, a mixture of 30ml of methanol and 5 ml of dilute hydrochloric acid (1/1) is added tothe reaction solution. The reaction solution is concentrated byevaporation under vacuum, and the residue is taken up in ethyl acetate.The organic phase that is obtained is extracted with water and washedwith sodium bicarbonate solution. After the solution is dried, and afterconcentration by evaporation under vacuum, 0.73 g (86% of theory) ofyellow crystals is obtained.

Stage 3 9α-Vinyl-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

Under inert gas atmosphere, 13.7 g (34.8 mmol) oftriphenylmethyl-phosphonium iodide and 1.0 g (34.8 mmol) of sodiumhydride (about 80% on paraffin oil) in 80 ml of DMSO is brought toreaction in an ultrasound bath at about 50° C. After 30 minutes, 0.73 g(2.3 mmol) of3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde,dissolved in 10 ml of DMSO, is added to the reaction solution, and themixture is allowed to react in an ultrasound bath for another 60minutes. After water is added, it is extracted with ethyl acetate, theorganic phase is washed with water, dried and concentrated byevaporation.

The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 0.59 g (81% of theory) after chromatography

Melting point: 214-220° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS): 9.00 (s, 3-OH); 6.96 (d, J=8.6 Hz, H-1);6.49 (dd, J=8.6/2.7 Hz, H-2); 6.41 (d, J=2.7 Hz, H-4); 6.29 (dd,J=17.2/10.5 Hz, —CH═CH₂); 5.00 (dd, J=10.5/1.9 Hz, —CH═CH₂ ; 4.48 (d,J=4.7 Hz, 16α-OH); 4.43 (dd, J=17.2/1.9 Hz, —CH═CH₂ ); 4.18 (m, 16β-H);2.68 (m, H-6); 0.72 (t, J=6.8 Hz, H-18a)

EXAMPLE 3 9α-(2′,2′-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diolStage 13,16α-Bis[perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-trieneanalogously to Example 1, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile.

Yield: 58% of theory

Stage 2 3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 1, stage 2 yields3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde;

Yield: 83% of theory

Stage 3 9α-(2,2-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13ml (0.77 mmol) of diethyl(difluoromethyl)-pbosphonate are introducedinto a reaction flask that was rendered inert, and cooled to about −75°C. After 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 M in pentane) isadded and after 30 minutes of reaction time, 0.14 g (0.31 mmol) of3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde, dissolved in amixture of 1.5 ml of dimethoxyethane/0.3 ml of pentane, is added to thereaction solution. The reaction solution is refluxed until the reactionis completed. After being added into cooled ammonium chloride solution,it is extracted with ethyl acetate. The organic phase is concentrated byevaporation under vacuum, the residue is taken up in 5 ml of methanoland mixed with 0.5 ml of dilute hydrochloric acid (1/1). Ethyl acetateis added to the reaction solution, the organic phase is washed withsodium bicarbonate solution and concentrated by evaporation undervacuum. The crude product that is obtained is purified by columnchromatography on silica gel (cyclohexane/ethyl acetate, 2/1).

Yield: 22 mg (21% of theory)

¹H-NMR (400 MHz, DMSO-d₆, TMS): 9.08 (s, 3-OH); 7.10 (d, J=8.6 Hz, H-1);6.51 (dd, J=8.6/2.3 Hz, H-2); 6.41 (d, J=2.3 Hz, H-4); 4.76 (dd,J=25.4/10.9 Hz, —CH═CF₂); 4.51 (d, J=4.69 Hz, 16α-OH); 4.25 (m, 16β-H);2.68 (m, H-6); 0.68 (s, H-18)

EXAMPLE 49α-(2′,2′-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16α-diolStage 13,16α-Bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-trieneanalogously to Example 1, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homoestra-1,3,5(10)-triene-9-carbonitrile.

Yield: 58% of theory.

Stage 2 3,16α-Dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrileanalogously to Example 1, stage 2 yields3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of theory

Stage 39α-(2,2-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

Reaction of3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde; Reactionconditions and execution of the reaction as well as molar ratios as inthe 3^(rd) stage of9α-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol.

The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate, 2/1) and crystallization from ethyl acetate.

Yield: 12% of theory

Melting point: 225-232° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS): 9.06 (s, 3-OH); 7.08 (d, J=8.6 Hz, H-1);6.50 (dd, J=8.6/2.7 Hz, H-2); 6.41 (d, J=2.7 Hz, H-4); 4.78 (dd,J=21.5/14.8 Hz, —CH═CF₂); 4.47 (d, J=4.50 Hz, 16α-OH); 4.18 (m, 16β-H);2.68 (m, H-6); 0.72 (t, J=6.8 Hz, H-18a)

EXAMPLE 5 17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol Stage 13,16α-Bis[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-trieneanalogously to Example 2, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene-9-carbonitrile.

Yield: 45% of theory

Stage 2 3,16α-Dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene-9-carbonitrileanalogously to Example 2, stage 2 yields3,16α-dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 83% of theory

Stage 3 17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Reaction of3,16α-dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehydeanalogously to Example 2, stage 3 yields17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol.

The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 51% of theory

Melting point: 94-98° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS); 9.02 (s, 3-OH); 6.97 (d, J=8.2 Hz, H-1);6.51 (dd, J=8.2/2.7 Hz, H-2); 6.42 (d, J=2.7 Hz, H-4); 6.22 (dd,J=17.2/10.5 Hz, —CH═CH₂); 5.09 (d, J=5.5 Hz, 16α-OH); 5.01 (dd,J=10.5/1.9 Hz, —CH═CH₂ ); 4.45 (dd, J=17.2/1.9 Hz, —CH═CH₂ ); 4.35 (dd,J=55.1/4.7 Hz, H-17α); 4.11 (m, 16β-H); 2.68 (m, H-6); 0.79 (d, J=1.9Hz, H-18)

EXAMPLE 6 17,17-Difluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diolStage 13,16α-Bis[perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-trieneanalogously to Example 2, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile.

Yield: 46% of theory

Stage 23,16α-Dihydroxy-17,17-difluoro-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrileanalogously to Example 2, stage 2 yields3,16α-dihydroxy-17,17-difluoro-estra-1,3,5 (10)-triene-9-carbaldehyde.

Yield: 88% of theory

Stage 3 17,17-Difluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Reaction of3,16α-dihydroxy-17,17-difluoro-estra-1,3,5(10)-triene-9-carbaldehydeanalogously to Example 2, stage 3 yields17,17-difluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol.

The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 75% of theory

¹H-NMR (400 MHz, CDCl₃, TMS): 7.08 (d, J=8.6 Hz, H-1); 6.63 (dd,J=8.6/2.7 Hz, H-2); 6.54 (d, J=2.7 Hz, H-4); 6.23 (dd, J=17.2/10.5 Hz,—CH═CH₂); 5.08 (dd, J=10.5/1.9 Hz, —CH═CH₂ ; 4.48 (dd, J=17.2/1.9 Hz,—CH═CH₂ ); 4.44 (m, 16β-H); 2.79 (m, H-6); 0.95 (d, J=1.9 Hz, H-18)

EXAMPLE 7 9α-(Hex-1′-enyl)-estra-1,3,5(10)-triene-3,16α-diol Stage 13,16α-Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-trieneanalogously to Example 2, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile.

Yield: 61% of theory

Stage 2 3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrileanalogously to Example 2, stage 2 yields3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of theory

Stage 3 9α-(Hex-1-enyl)-estra-1,3,5(10)-triene-3,16α-diol

8.68 g (20 mmol) of pentyltriphenyl-phosphonium bromide+sodium amide (1g contains 2.3 mmol of pentyltriphenyl-phosphonium bromide), 0.2 g (0.67mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 mlDMSO are introduced into a reaction flask that was rendered inert. Thereaction mixture is treated for about 2 hours in an ultrasound bath at60° C., After the reaction is completed, water is added to the reactionsolution. The crude product is isolated by extraction with ethylacetate, washing of the organic phase with water and concentration byevaporation until a dry state is reached.

The crude product that is obtained is purified by column chromatographyon silica gel (cyclohexane/ethyl acetate, 1/1) and crystallization fromethyl acetate.

Yield: 0.18 g (75% of theory) according to chromatography

Melting point: 166-168° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS): 8.97 (s, 3-OH); 7.08 (d, J=8.6 Hz, H-1);6.49 (dd, J=8.6/2.7 Hz, H-2); 6.41 (d, J=2.7 Hz, H-4); 5.73 (d, J=12.5Hz, —CH═CH—CH₂—); 5.20 (dt, J=12.5/7.4 Hz, —CH═CH—CH₂—); 4.48 (d, J=4.7Hz, 16α-OH); 4.24 (m, 16β-H); 2.66 (m, H-6); 0.68 (t, J=7.0 Hz, CH₃—CH₂—); 0.66 (s, H-18)

EXAMPLE 8 9α-(But-1′-enyl)-estra-1,3,5(10)-triene-3,16α-diol Stage 13,16α-Bis[perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-trieneanalogously to Example 2, stage 1 yields3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile.

Yield: 52% of theory

Stage 2 3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde

Reaction of3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrileanalogously to Example 2, stage 2 yields3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of theory

Stage 3 9α-(But-1-enyl)-estra-1,3,5(10)-triene-3,16α-diol

8.68 g (20 mmol) of propyltriphenyl-phosphonium bromide+sodium amide (1g contains 2.3 mmol of propyltriphenyl-phosphonium bromide), 0.2 g (0.67mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 mlof DMSO are introduced into a reaction flask that was rendered inert.The reaction mixture is treated for about 2 hours in an ultrasound bathat 60° C. After the reaction is completed, water is added to thereaction solution. The crude product is isolated by extraction withethyl acetate, washing of the organic phase with water, andconcentration by evaporation until a dry state is reached.

The crude product that is obtained is purified by column chromatographyon silica gel (cyclohexane/ethyl acetate, 1/1).

Yield: 0.16 g (73% of theory) after chromatography

Melting point: 140-148° C.

¹H-NMR (400 MHz, DMSO-d₆, TMS); 8.98 (s, 3-OH); 7.09 (d, J=8.6 Hz, H-1);6.49 (dd, J=8.6/2.7 Hz, H-2); 6.41 (d, J=2.7 Hz, H-4); 5.70 (d, J=12.5Hz, —CH═CH—CH₂—); 5.19 (dt, J=12.5/7.4 Hz, —CH═CH—CH₂—); 4.47 (d, J=4.7Hz, 16α-OH); 4.24 (m, 16β-H); 2.66 (m, H-6); 0.66 (s, H-18); 0.57 (t,J=7.2 Hz, CH₃ —CH₂—)

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding German application No. 102 26 326.4,filed Jun. 11, 2002, and U.S. Provisional Application Ser. No.60/443,868, filed Jan. 31, 2003, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1-19. (canceled)
 20. A method for therapy of anestrogen-deficiency-induced bone mass loss in-vivo treatment of femaleinfertility; in-vitro treatment of female infertility; hormonereplacement therapy in a patient in need of replacement of estrogen;therapy of hormone-deficiency-related symptoms in a patient with ovariandysfunction, wherein said patient is in need of replacement of estrogen;treatment of polycystic ovary syndrome, or premature ovarian failuresyndrome; treatment of a peri or postmenopausal symptom or condition,which is hot flashes, sleep disorders, irritability, mood fluctuations,incontinence, vaginal atrophy or hormone-deficiency-related emotionaldisorders; treatment of rheumatoid arthritis, multiple sclerosis, lupus,or Crohn's disease; treatment of psoriasis; treatment of endometriosis;treatment of asthma; therapy of hormone-deficiency-related bone massloss; therapy of osteoporosis; treatment of arteriosclerosis; treatmentof high blood pressure; treatment of Alzheimers disease or anestrogen-deficiency-related impairment of memory and learning; ortherapy of prostate hyperplasia; comprising administering to a patientin need thereof an effective amount of a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a 9α-Substitutedestra-1,3,5(10)-triene compound of formula I

wherein R³ is hydrogen or R¹⁸, R¹⁸ is a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to6 carbon atoms, a trifluoromethyl group, an optionally substituted aryl,heteroaryl or aralkyl radical, an acyl radical COR¹⁹, or iR SO₂, R¹⁹ isan optionally substituted, straight-chain or branched-chain hydrocarbonradical with up to 10 carbon atoms that is saturated or unsaturated inup to three places and is optionally partially or completelyhalogenated, R²⁰ is R²¹R²²N, R²¹ and R²² are, independently of oneanother, a hydrogen atom, a C₁-C₅-alkyl radical, or C(O)R²³, R²³ is anoptionally substituted, straight-chain or branched-chain hydrocarbonradical with up to 10 carbon atoms that is saturated or unsaturated inup to three places and is optionally partially or completelyhalogenated, an optionally substituted C₃-C₇-cycloalkyl radical, anoptionally substituted C₄-C₁₅-cycloalkylalkyl radical or an optionallysubstituted aryl, heteroaryl or aralkyl radical, or, together with the Natom, a polymethylenimino radical with 4 to 6 C atoms or a morpholinoradical, R⁷ and R^(7′) are, in each case independently of one another, ahydrogen atom or a halogen atom, R⁹ is a straight-chain orbranched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms,which is optionally partially or completely fluorinated, or an ethinylor prop-1-inyl radical, R¹³ is a methyl group or an ethyl group, R¹⁶ isa hydroxy group or R¹⁸O—, R²⁰SO₂—O— or OC(O)R²³, and R¹⁷ and R^(17′)are, in each case independently of one another, a hydrogen atom or ahalogen atom, pharmaceutically acceptable salt thereof.
 21. A methodaccording to claim 20, wherein in the compound of formula I, R³ is ahydrogen atom.
 22. A method according to claim 20, wherein in thecompound of formula I, R⁷ is a hydrogen atom or an α-position fluorineatom, R⁹ is a vinyl, ethinyl or prop-1-inyl group, R¹⁶ is a hydroxygroup, and R¹⁷ is a hydrogen atom or an α-position fluorine atom.
 23. Amethod according to claim 20, wherein in the compound of formula I, R¹⁶is R¹⁸—O— or R²⁰SO₂—O—.
 24. A method according to claim 20, wherein thecompound of formula I is 9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol9α-Allyl-estra-1,3,5(10)-triene-3,16α-diol18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol3-Methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol9α-Allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol18a-Homo-3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol18a-Homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol9α-(2′,2′-Difluorovinyl)-estra-1,3,5 (10)-triene-3,16α-diol9α-(2′,2′-Difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16α-ol16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate9α-Allyl-estra-1,3,5 (10)-triene-3,16α-diyl-disulfamate18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-N-acetyl)-sulfamate18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)sulfamate9α-(Prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α-diol9α-(n-Propyl)-estra-1,3,5(10)-triene-3,16α-diol9α-Ethinyl-estra-1,3,5(10)-triene-3,16α-diol9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate16α-Valeroyloxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol16α-Acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol18a-Homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol7α-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol7α-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol17β-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol18a-Homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol18a-Homo-7α-fluoro-9αallyl-estra-1,3,5(10)-triene-3,16α-diol18a-Homo-17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol or18a-Homo-17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol.
 25. Amethod according to claim 20, which is for hormone replacement therapyin a patient in need of replacement of estrogen, and which furthercomprises administering a SERM or raloxifene.
 26. A method according toclaim 20, which is for therapy of an estrogen-deficiency-induced bonemass loss.
 27. A method according to claim 20, which is for therapy ofosteoporosis.
 28. A method according to claim 20, which is for thetreatment of endometriosis.
 29. A method according to claim 24, which isfor the treatment of endometriosis.
 30. A method according to claim 20,wherein the compounds administered is17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol.
 31. A methodaccording to claim 30, which is for the treatment of endometriosis.